Iron serves as an important cofactor of iron-containing proteins that play critical roles in the maintenance of DNA stability and cell cycle progression. The disturbed iron homeostasis results in the pathogenesis of many diseases such as cancer and anemia. In this study, we found a clear correlation between iron deficiency and intervertebral disc degeneration (IDD). Through microarray experiments, we found that a large number of genes were differentially expressed in tissues with different degrees of degeneration. Among them, an iron-containing gene, PolE, the catalytic subunit of DNA polymerase epsilon (Polε), and the other two Polε subunits, including PolE2 and PolE3, were markedly downregulated, while some proteins involved in apoptosis such as Caspase-3 and -8 were significantly upregulated. By supplementation with an iron chelator deferoxamine (DFO) or knocking down either iron divalentmetal transporter 1 (DMT1) or transferrin receptor 1 (TfR1) in the nucleus pulposus (NP) cells, we found that the protein levels of PolE complex members were dramatically reduced, whereas the intrinsic apoptotic pathway was activated. Interestingly, overexpression of PolE in NP cells knocked down with either DMT1 or TfR could not reverse the stability of PolE complex and apoptosis status. In summary, our study suggests that iron deficiency is an important factor in the aggravation of IDD. Proper iron supplementation may be an effective strategy to alleviate the symptoms of patients with IDD.